PROJECT SUMMARY Opioid drugs are powerful analgesics, but their side-effect profile strongly limits their use. Indeed, their addictive properties have led to an epidemic of abuse in the US that accounts for 80% of the global utilization of prescription opioid analgesics in the US, with a market of over $11 billion per year. Previous studies have shown that the endocannabinoid neurotransmitter, anandamide, controls nociception in mammals through a predominantly peripheral mechanism. The biological actions of anandamide are terminated by the enzyme fatty acid amide hydrolase (FAAH). We have recently discovered a novel class of small-molecule inhibitors that block FAAH activity exclusively outside the central nervous system (CNS). The prototype member of this class, URB937, exerts profound and long-lasting analgesic effects in a variety of animal models, suggesting that peripheral FAAH inhibition may offer a transformative approach to pain therapy by providing a means to reduce the need for opioid analgesics. Previous selectivity, safety and pharmacokinetics studies have identified URB937 as a lead candidate for preclinical development. The present proposal will assess the pharmacodynamics interactions between URB937 and opioids in two sets of mouse and rat models. (1) Chronic pain models. We will compare the analgesic effects of different dosages of URB937 and two commonly abused opioid analgesics, hydrocodone and oxycodone, in two preclinical models of chronic neuropathic and inflammatory pain. Sub-effective and median effective (ED50) doses of each compound will be selected and combined to investigate potential synergistic effects. Potential sex-specific differences will also be explored. (2) Models of opiate addiction and constipation. We will examine the effects of URB937 on three unwanted effects caused by the administration of opioid analgesics, which could be affected by the combination of both drugs: self-administration, withdrawal, and constipation. If the proposed activities show that (i) the analgesic actions of URB937 are synergistic with those of oxycodone and hydrocodone; and (ii) URB937 does not aggravate the side effects of these opioid drugs, we will seek further funding in the private or public financial market for the preclinical development of URB937 as an opioid-sparing analgesic for chronic pain.